1. Field of the Invention
The invention generally relates to the fields of molecular biology and oncology. More specifically, it relates to the identification of a new tumor suppressor gene (TSG) designated hippo and the corresponding polypeptide. Uses for hippo in diagnosis and therapy of cancer are provided.
2. Related Art
During metazoan development, cell-intrinsic and -extrinsic factors act coordinately to specify the characteristic size and number of diverse cell types (Conlon and Raff, 1999; Stocker and Hafen, 2000). The final number of cells in an organ or organism is determined by the balanced act of cell proliferation and cell death (apoptosis). A challenge is to understand how these processes are coordinated in normal development and how aberrant regulation of this coordination leads to pathological conditions such as cancer.
The relationships between cell proliferation and cell death are complex. It has long been observed that increased proliferation due to activation of oncogenes such as Myc or Ras is often accompanied by increased apoptosis (reviewed in Green and Evan, 2002). This has led to the proposal that apoptosis act as a built-in failsafe to prevent “inappropriate” proliferation of somatic cells (Green and Evan, 2002). Thus, sustained growth of cancer cells not only requires activation of the cell proliferation machinery, but also suppression of the apoptotic failsafe mechanisms. In most cases, this is brought about by coupling oncogene activation with antiapoptotic lesions such as overexpression of Bcl-2 or loss of p53 (Green and Evan, 2002). However, it is also possible that there exist gene networks that couple proliferation to apoptosis in such a manner that loss of a single gene may simultaneously promote proliferation and suppress apoptosis.
The compound eye of Drosophila provides an excellent model to decipher the mechanisms that coordinate cell proliferation and apoptosis. This highly organized structure develops from the eye imaginal disc wherein cell proliferation and apoptosis occurs in a stereotyped manner (Wolff and Ready, 1993). Cells divide asynchronously during early larval periods. Starting in the mid-third instar larval stage, a morphogenetic furrow (MF) moves across the eye imaginal disc from posterior to anterior. Cells anterior to the MF are undifferentiated and divide asynchronously, whereas cells in the MF are synchronized in the G1 phase of the cell cycle. Posterior to the MF, cells either exit the cell cycle and differentiate or undergo one round of synchronous division (second mitotic wave, SMW) before differentiation. These cells assemble into approximately 750 ommatidia, leaving behind approximately 2000 superfluous cells that are eliminated by a wave of apoptosis ˜36 hr after puparium formation (APF) (Wolff and Ready, 1993).
Previous studies have identified cyclin E (CycE) and DIAP1 as key regulators of cell cycle and apoptosis, respectively (Richardson et al., 1995; Hay et al., 1995). Cell cycle exit requires the downregulation of CycE/cdk2 activity, while DIAP1 functions by inhibiting the proapoptotic caspases. That coordinated regulation of cyclin E and DIAP1 might play a critical role organ size control is supported by recent studies of the Drosophila tumor suppressor gene salvador (sav, also called shrp), which encodes a protein containing WW and coiled-coil domains (Tapon et al., 2002; Kango-Singh et al., 2002). Loss of sav leads to increased cell proliferation and decreased apoptosis associated with elevated levels of CycE and DIAP1 proteins. Interestingly, Sav associates with the Warts (Wts, also called Lats) protein kinase, suggesting that Sav and Wts might function in a common signaling pathway (Tapon et al., 2002). Indeed, loss of wts also leads to increased cell proliferation and decreased apoptosis (Tapon et al., 2002). At present, little is known about the molecular architecture of this signaling pathway.